Polysymptomatology in Pediatric Patients Receiving Palliative Care Based on Parent-Reported Data

Key Points Question What symptoms do pediatric patients receiving palliative care experience, and how frequent and severe are the symptoms, according to parent report? Findings In this cross-sectional analysis of 501 pediatric patients receiving palliative care, at baseline, parents reported a mean (SD) of 6.7 (3.4) symptoms per patient; although older patients had more symptoms and higher symptom scores, variation across disease categories was relatively minor. Patients in the upper 10th percentile of symptom frequency and severity scores had a median of 12 symptoms. Meaning This study suggests that assessment and management of polysymptomatology is a critical aspect of pediatric palliative care.


Introduction
Symptom assessment and management are foundational aspects of pediatric palliative care (PPC). 1 Pediatric palliative care serves patients with a wide variety of severe illnesses and complex chronic conditions (CCCs) from birth to young adulthood and works to deliver care that addresses patients' health care needs and aligns with patient and family goals. 2,3For children receiving home-based PPC services, parents' top priority was the physical care of the child, including symptom management. 4 parents and PPC clinicians can attest, children receiving PPC experience an array of symptoms, often concurrently, and uncontrolled symptoms undermine both comfort and quality of life for children and their parents. 5ong patients receiving PPC, many basic but important questions regarding symptomsincidence, prevalence, severity, and co-occurrence-have either no empirically based answers or answers limited to a particular group of patients or to physician-reported assessments. 6What is clear, given the existing evidence, is that, among children with serious illness, significant symptoms are common, often to a degree that is distressing to the patients and their caregivers.Among children with advanced cancer, parents and self-reporting patients often report substantial pain, fatigue, drowsiness, and irritability. 7,8Parents of children with serious central nervous system impairment report that their children experienced a mean of 3.2 symptoms, and at least half the children experienced pain or irritability, sleep problems, and gastrointestinal symptoms such as nausea and vomiting. 9Pediatric palliative care physicians report that substantial proportions of their patients experience cognitive impairment, speech impairment, sleep and fatigue problems, irritability, and pain. 10 this study, we sought to characterize the point prevalence, frequency, and severity of specific symptoms and the co-occurrence of symptom, among a large, diverse sample of patients receiving PPC.To do so, we analyzed baseline data from 501 patients enrolled in an ongoing cohort study, using a structured parent-report symptom assessment tool of 20 symptoms.Given the widely held beliefs among clinicians that symptoms among patients receiving PPC vary depending on underlying conditions and by age, we examined whether symptom metrics differed across patients with different CCCs and across age groups.Of the 641 eligible patients and parents approached regarding the study, 501 (78.2%) agreed to participate and completed at least background information (including race and ethnicity, selfidentified by participants, to assess for possible disparities in PPC [11][12][13][14] ) and the symptom assessment measure from the baseline instruments.

Data Collection
At study entry, parents completed a set of instruments either in a clinical care setting or at home, with data recorded on either paper or internet-based forms.Paper forms were subsequently double entered by study staff into the internet-based forms.

Symptom Assessment Measure
Parent report of the child's symptoms during the prior 7 days was measured using the previously validated Memorial Symptom Assessment Scale (MSAS) adapted for children 15 and further adapted (PediQUEST [PQ]-MSAS) for children with serious illness.Symptom scores for each symptom were calculated by adapting and modifying methods previously used 7,16,17 to account for assessment differences of specific symptoms and between the age groups.
Specifically, a patient's symptom score for each symptom was calculated as the mean of frequency and severity values for the symptoms in which both these attributes were assessed, as the severity score for the 3 symptoms for which only severity was uniformly assessed, and as the overall mean symptom score value among symptomatic patients for the 2 symptoms for which neither severity nor frequency was assessed (seizures and bleeding in the older age group).An individual's total symptom score was the mean of all of the separate transformed symptom scores and could range from 0 to 100.

CCC Designation
Enrolled patients' medical record numbers were used to match study participants with their data in the Pediatric Hospital Information System (PHIS; Children's Hospital Association) administrative database.Of the 501 participants, 472 had matching Pediatric Hospital Information System data, which included diagnoses recorded as International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Clinical Modification codes for any hospitalizations that occurred during the year prior to the date of baseline assessment completion and which were used to identify whether participating patients were included in any of the 12 different non-mutually exclusive CCC categories. 18For patients with no Pediatric Hospital Information System data, CCC categories were identified via medical record review.

Statistical Analysis
Missing data in the variables used in this analysis were minimal (

Results
Among the first 501 patients receiving PPC enrolled in SHARE ( Although the mean (SD) scores were slightly higher than average for patients who were technology dependent and were highest among patients who had metabolic CCCs (21.3 [11.5]) and lower among patients with transplant CCCs (18.6 [11.9]), the mean scores ranged by only 3 points across all of the CCC categories.
We also examined the symptom scores for each symptom across patients with each of the CCC category diagnoses, for all patients (both asymptomatic and symptomatic) and for just patients who were experiencing the symptom (symptomatic).Figure 3 provides a bar graph for the 6 most commonly reported symptoms.Although the symptom scores differed slightly for all patients across the CCC categories, these differences were mostly due to different symptom prevalences in each CCC category.Examining the symptom scores among only the patients who were symptomatic, the mean symptom score for each symptom was essentially the same across CCC categories.For example, focusing on shortness of breath, among patients with malignant neoplasm CCCs, the prevalence was notably less, but among patients who were symptomatic, the intensity was the same as other CCC categories.
Last, given the association of patient age with symptom counts and scores, we stratified patients into 4 age groups (corresponding closely to defined age stages 19 ; 0-11 months, 1-9 years, 10-17 years, and Ն18 years), thereby allowing for potential nonlinear symptom and age associations to be detected, and we plotted a 2-way gradient of patients' total number of symptoms and total symptom scores, identifying the top 10th percentile of patients regarding total symptom scores (Figure 4).Patients in this most symptomatic group had a median of 12.0 symptoms (IQR, 11.0-13.0),which had a mean (SD) severity and frequency scores of 42.0 (7.1) (indicating ratings just below "moderate" and "sometimes").This group of patients had been receiving PPC services for a mean (SD) of 279 (557) days, compared with a mean (SD) of 372 (797.5)days for all other patients, but this difference was not statistically significant owing to the wide variation in both groups.

Discussion
Parent-reported symptom data from a large cohort of 501 patients receiving PPC at 7 different children's hospitals the United States reveal that these patients experience a wide variety of symptoms of various frequencies and levels of severity.A total of 73.3% of patients experienced polysymptomatology, consisting of 5 or more symptoms (analogous to the count of medications for the definition of polypharmacy 20 ).Markedly elevated total symptom scores among many of the patients suggest substantial symptom-related comorbidity, tending to increase from a mean (SD) total symptom score of 12.3 (9.5) among infants younger than 1 month of age to a mean (SD) score of 24.5 (12.8) among patients 18 years or older.Five aspects of our findings warrant discussion.First, similar to previous research, we found that parents of children with a life-threatening illness report that many of these children experience severe or frequent symptoms, with pain, fatigue, irritability, and shortness of breath being most common. 7,8,15,21Our results differ somewhat from reports of children with progressive conditions, which found that the most prevalent symptoms included behavioral symptoms such as agitation, 22 feeding problems, 9 and sleep difficulties, 9 but these differences may have more to do with differing terminology for the same symptoms (such as irritability vs agitation) or with different assessments of similar underlying or overlapping constructs (such as loss of appetite vs feeding difficulties).Our results also differ somewhat from those of a study of children with cancer that found that the most  prevalent symptoms included loss of appetite and nausea, 23 but they are similar to those of a previous study of children with advanced cancer, wherein pain and low energy were the most prevalent symptoms. 7These findings suggest that symptom profiles may vary depending on underlying conditions (and their treatments) but that symptoms for a variety of advanced serious illnesses converge on a set of common presentations.
Second, among patients receiving PPC, 1 group experiences very high total symptom scores (Figure 4).Furthermore, the fact that neither the number of symptoms present nor the total symptom score was associated with the duration of time that a patient has been receiving PPC services argues that further improvements in symptom assessment and effective management are needed.Steps in this direction should include the development of practice guidelines, quality improvement efforts, and clinical research. 6ird, most of the patients experience polysymptomatology.This was observed for all age groups (except neonates <1 month), among patients who had diagnoses in each of the different (but non-mutually exclusive) CCC categories, and among all patients with 2 or more CCC diagnoses.
Polysymptomatology underscores the need for systematic assessment because the symptom that might be evident to the clinician is likely not the only symptom and may not be the most problematic one from the patient or parent perspective. 24Once accurate inventory and assessment of all present symptoms have been made, polysymptomatology also raises the likely need to prioritize symptom management interventions, potentially posing tradeoffs whereby the effective management of one symptom may make another symptom worse.Clinical management optimization may require using fewer medications to minimize the risks of complex polypharmacy regimens. 25 3), if a symptom was present, that symptom's score was similar across all patients with that symptom (Figure 3).
Fifth, these findings highlight important additional questions and issues to be surmounted.The potential bidirectional association between child symptoms (as reported by parents) and parent mental well-being needs to be better understood.Identification of symptom clusters among pediatric patients may yield insights to guide clinical investigations and management. 26Studies of longitudinal symptom and symptom cluster trajectories, and how these are associated with specific treatments, are critical. 27Expanding studies to include parents who speak languages other than English and Spanish is important.

Strengths and Limitations
This study has strengths and limitations.Like patient-reported outcomes data, parent-reported data regarding a child's symptoms offer a complementary, if not more accurate and superior, view of a child's experience, compared with clinician-reported data. 5,28Both parent and clinician assessment of symptoms in infants and in older patients who are unable to communicate are challenging, especially for symptoms such as low energy or dry mouth, which may not have clear observable manifestations. 29,302][33][34][35] Given that having a child receiving palliative care services also negatively affects the mental state of parents, [36][37][38][39] a set of complex reciprocal relationships between child and parent are likely encoded into parent-reported data. 40 This cross-sectional study used parent-reported baseline data from the ongoing Pediatric Palliative Care Research Network's Shared Data and Research (SHARE) 2-year prospective cohort study being conducted at 7 children's hospitals across the United States.Patients were eligible if they were receiving PPC services and were younger than 30 years.Parents were eligible to participate if they were responsible for the patient, at least 18 years of age or a minor permitted by state law to consent for their own participation, and able to speak and understand English or Spanish.Institutional review boards at The Children's Hospital of Philadelphia Research Institute, Boston Children's Hospital, Seattle Children's Research Institute, and Children's Minnesota approved the conduct of this study.Parents and competent patients 18 years or older provided written informed consent.This study JAMA Network Open | Pediatrics Parent-Reported Polysymptomatology in Pediatric Patients Receiving Palliative Care JAMA Network Open.2021;4(8):e2119730.doi:10.1001/jamanetworkopen.2021.19730(Reprinted) August 5, 2021 2/13 Downloaded From: https://jamanetwork.com/ on 09/19/2023 followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.Enrollment began April 10, 2017, and ended December 18, 2020.The current sample represents the first 501 patients who enrolled and had evaluable baseline data collected by February 5, 2020.

Figure 2 .
Figure 2. Frequency of Patients With Different Numbers of Reported Symptoms Differences in the number of symptoms and in the total symptom score by demographic and clinical characteristics were assessed using 2-tailed t tests, analysis of variance, and linear regression.Scatterplots, box and whisker plots, bar charts, and radar plots were generated to display symptom point prevalence, frequency, and severity across the sample and by age group and CCC category.An ordinary least-squares regression model was used to assess patients' total symptom scores as a function of their symptom counts and age groups; for these analyses, α was set at .05.All statistical analyses were performed using Stata, version 16.0 (StataCorp).
Table), the median age was 4.1 years (interquartile range, 0.8-12.9years).Patients were primarily male (267 [53.3%]) and were identified by their parents as White (356 [71.1%]),Black (42 [8.4%]), Asian (15 [3.0%]), Native population (American Indian, Native Hawaiian, and/or Alaska Native; 25 [5.0%]), or other/multiple race (63 [12.6%]); 75 patients (15.0%) were identified as Hispanic.Patients' health insurance coverage was government issued (205[40.9%]), private (154 [30.7%]), or both government and private (131 [26.2%]); 5 parents (1.0%) reported no insurance, and 6 (1.2%) either chose not to disclose or had an unspecified other form of insurance.Patients had been receiving PPC services on average for 1 year (mean, 363 days; range, 1 day to 14.6 years; eFigure in Supplement 1).Most patients (438 [87.4%]) were technology dependent (Table), and all patients had CCC diagnoses.The most prevalent (nonmutually exclusive) CCC categories were gastrointestinal (357 [71.3%]), cardiovascular (310 [61.9%]), and neurologic (289 [57.7%]).Patients had a median of 6 different CCC categories of diagnoses (interquartile range [IQR], 4-7 CCC categories).Among the 501 patients, according to parent report at the time of study entry, 488 (97.4%) were experiencing at least 1 of the 20 assessed symptoms.The point prevalences of these specific symptoms ranged broadly (Figure1), with the 5 most prevalent symptoms being pain (319 [63.7%];As reported by parents, patients were experiencing a mean (SD) of 6.7 (3.4) of the 20 symptoms (Table).A total of 367 patients (73.3%) had 5 or more symptoms.The number of symptoms increased steadily with increasing patient age and with regard to the amount of time receiving PPC services prior to enrollment; no associations were observed regarding sex, race, or ethnicity categories.Differences in the distribution of the number of different symptoms by patient clinical characteristics can be examined graphically in Figure2.Figure2Ashows the overall distribution of symptoms, plotted as a histogram and as a box plot, with a median of 7 symptoms (IQR, 4-9 symptoms).Figure2Bshows the same box plot, stratified by patients who had specific categories of CCCs, with the number of patients in each strata annotated at the end of each upper range.Across Regarding patients' total symptom scores (the mean of symptom scores, rescaled on a 0-100 range) across the full sample, these scores ranged from 0 to 63.8 with a mean (SD) of19.6 (11.7).Differences in total symptom scores by patient characteristics are also reported in the Table.These scores increased steadily with increasing patient age; no associations were observed regarding sex, race, or ethnicity categories, nor regarding time receiving PPC services (eFigure in Supplement 1).JAMA Network Open.2021;4(8):e2119730.doi:10.1001/jamanetworkopen.2021.19730(Reprinted) August 5, 2021 4/13 Downloaded From: https://jamanetwork.com/ on 09/19/2023

Table .
Patient Characteristics and Symptoms cThe t test was used to assess differences of means for patients with each specific CCC type of diagnoses that differed from the mean of all other patients without that specific CCC type of diagnoses.d Ordinary least-squares linear regression was used to test whether the mean values increased as the number of CCCs increased.JAMA Network Open | Pediatrics Parent-Reported Polysymptomatology in Pediatric Patients Receiving Palliative Care JAMA Network Open.2021;4(8):e2119730.doi:10.1001/jamanetworkopen.2021.19730(Reprinted) August 5, 2021 5/13 Downloaded From: https://jamanetwork.com/ on 09/19/2023 Figure 1.Point Prevalence of 20 Symptoms Based on Parent Report JAMA Network Open.2021;4(8):e2119730.doi:10.1001/jamanetworkopen.2021.19730(Reprinted) August 5, 2021 6/13 Downloaded From: https://jamanetwork.com/ on 09/19/2023 Figure 3. Symptom Scores Across Categories of Complex Chronic Conditions, for All Patients and Only Symptomatic Patients Downloaded From: https://jamanetwork.com/ on 09/19/2023 Downloaded From: https://jamanetwork.com/ on 09/19/2023 9hich symptoms, lower levels of disruption of function or reduction of quality of life, can simply be tolerated.Fourth, our observed mean symptom count of 6.7 symptoms is greater than a previous study's mean of 3.2 symptoms,9most likely because we assessed 20 possible symptoms compared with the 7 possible symptoms in the previous study.When we restricted our symptom count to only 7 symptoms, similar to those assessed in the previous study (pain, difficulty sleeping, vomiting, constipation, shortness of breath, seizures, and drowsiness), our sample's mean symptom count was 2.9.This finding underscores the importance that how symptoms are assessed (in clinical practice or research studies) is associated with the ensuing data.Furthermore, we observed that patients with different CCC categories were reported to be experiencing approximately the same number of symptoms and total symptom scores.Although the prevalence of different specific symptoms varied across CCC categories (eg, see the lower prevalence of cough among patients with malignant neoplasm CCCs or the lack of energy among infants with neonatal CCCs in Figure Fewer medications can be achieved in part by selecting medications that ameliorate more than 1 symptom, in part by avoiding medications when nonpharmacologic interventions are effective and in part by decidingFigure 4. Association of Symptom Counts With Total Symptom Score, Stratified by Age Group JAMA Network Open.2021;4(8):e2119730.doi:10.1001/jamanetworkopen.2021.19730(Reprinted) August 5, 2021 9/13 Downloaded From: https://jamanetwork.com/ on 09/19/2023